Immunoglobulins, the major secretory products of the adaptive immune system, include the IgG subclass, which identifies and neutralizes foreign cells. As adaptors, IgG activate an immune response by simultaneously binding antigens through their variable domains (F(ab)2) and through interaction of their Fc domain with Fcγ receptors (FcγR) on immune cells. The human FcγR family consists of the activating receptor FcγRIIIA (CD16) that mediates antibody-dependent cellular cytotoxicity (ADCC). The binding of IgG to CD16 is sensitive to the presence of glycosylation at a single site on asparagine 297 (N297) in its Fc domain, with a loss of binding observed after cleaving or preventing Fc glycosylation. The nature of the glycans attached to N297 varies the affinity of the CD16 interaction and thus governs antibody cytotoxicity. It has been suggested that IgG play a role in motor neuron degeneration. This was based on the finding of IgG deposit on the spinal cord and brain of patients with amyotrophic lateral sclerosis (ALS) and in animal models of inherited ALS. It was further found in animal models, that IgG from ALS patients could not be up-taken by motor axon terminals, after removing the IgG Fc domain. Consequently, it appears that FcγRs are involved in IgG deposition or in uptake by motor neurons.
ALS is a fatal neurodegenerative disease caused by degeneration of the upper and lower motor neurons. ALS patients and animal models of inherited ALS, like mutant Cu/Zn superoxide dismutase (mSOD1), display similar inflammatory responses at the site of the motor neuron injury, enabling both the CNS resident and systemic inflammatory cells to balance between neuroprotection and neurotoxicity. One population involved in these inflammatory responses is microglia cells, which during their activation change morphology, surface receptor expression, and produce growth factors and cytokines, leading to neuron protection or injury depending on the physiological conditions. The manners in which the signals switch between protective to cytotoxic microglia are not yet fully understood. However, ALS progression is attributed, in part, to cytotoxic microglia cells, which secrete proinflammatory cytokines leading to neuron damage. Cumulative, data demonstrate that Toll-like receptors or T-cells interacting with microglia are involved in inducing cytotoxic microglia, but data relating FcγR to microglia activity in ALS are scarce. Notably, the data known so far link the FcγR to phagocytosis by activated microglia in other neurodegenerative diseases, like Alzheimer's disease.
It would be beneficial to have an effective and selective treatment for ALS, which is as yet unavailable.